The SARM1 toll/interleukin-1 receptor domain possesses intrinsic NAD(+) cleavage activity that promotes pathological axonal degeneration
Open accessAbstract
Axonal degeneration is an early and prominent feature of many neurological disorders. SARM1 is the central executioner of the axonal degeneration pathway that culminates in depletion of axonal NAD+, yet the identity of the underlying NAD+-depleting enzyme(s) is unknown. Here, in a series of experiments using purified proteins from mammalian cells, bacteria, and a cell-free protein translation system, we show that the SARM1-TIR domain itself has intrinsic NADase activity-cleaving NAD+ into ADP-ribose (ADPR), cyclic ADPR, and nicotinamide, with nicotinamide serving as a feedback inhibitor of the enzyme. Using traumatic and vincristine-induced injury models in neurons, we demonstrate that the NADase activity of full-length SARM1 is required in axons to promote axonal NAD+ depletion and axonal degeneration after injury. Hence, the SARM1 enzyme represents a novel therapeutic target for axonopathies. Moreover, the widely utilized TIR domain is a protein motif that can possess enzymatic activity.
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Sarm1 TIR domain cleaves NAD+ into cyclic ADP-ribose (cADPR) as a new class of NAD+ hydrolases.
“Subsequent work showed that Sarm1 TIR domain cleaves NAD + into cyclic ADP-ribose (cADPR) as a new class of NAD + hydrolases 10,44”
From NAD+ hydrolase Sarm1 is a key driver of synapse degeneration and memory loss in Alzheimer’s disease (2025) · cites this paper as [44]
SARM1 NADase activity may contribute to axonal degeneration and is a potential target for therapeutic intervention in neurodegenerative diseases.
“The NADase activity of SARM1 may contribute to its role in axonal degeneration (Essuman et al., 2017) and is therefore a potential target for therapeutic intervention in neurodegenerative diseases.”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Essuman et al., 2017
SARM1 cleaves NAD+ into NAM, ADPR, and cADPR via its TIR domain and is expressed in brain and non-brain tissues including liver.
“SARM1 is a newly recognized class of NADase that cleaves NAD+ into NAM, ADPR, and cADPR via its TIR domain. It is expressed in both brain and non-brain tissues, including the liver (Essuman et al., 2017; Pan and An, 2018).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Essuman et al., 2017
The enzymatic activity of SARM1 relies on the Toll/interleukin receptor (TIR) domain, which was previously not known to possess catalytic activity.
“The enzymatic activity of SARM1 (FIG. 2c) relies on the Toll/interleukin receptor (TIR) domain that was previously not known to possess catalytic activity and generally to be involved in protein–protein interaction59.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [59]
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“It has multiple enzyme activities, including both the degradation and cyclisation of NAD and NADP, and base exchange activity that switches the nicotinamide of either coenzyme for another pyridine base [57, 58].”
BackgroundTakaso, Y., Noda, M., Hattori, T., Roboon, J., Hatano, M., Sugimoto, H., Brenner, C., Yamamoto, Y., Okamoto, H., Higashida, H., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-73984-3 · Cited by 17 · see citing works
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Fan, F., Joshi, P., Liu, X., Kotturu, S. K., Abiola, M., Liu, Q., & Lou, X. (2025) · doi:10.64898/2025.12.21.695860
- Authors
- Essuman, K., Summers, D. W., Sasaki, Y., Mao, X., DiAntonio, A., & Milbrandt, J.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- DiAntonio, Aaron
- Milbrandt, Jeffrey
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2017-03
- Volume
- 93
- Issue
- 6
- Pages
- 1334-1343.e5
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC6284238
- OpenAlex
- W2602599682
- Cited by
- 619
- References
- 45
- Citations by year
- 2026: 54 · 2025: 71 · 2024: 67 · 2023: 70 · 2022: 109 · 2021: 95 · 2020: 70 · 2019: 42 · 2018: 32 · 2017: 8
- FWCI
- 20.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 386 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (P41 GM103422)
- Muscular Dystrophy Association (MDA344513, MDA349925)
- National Center for Advancing Translational Sciences (UL1 TR000448)
- Institute of Clinical and Translational Sciences
- Alvin J. Siteman Cancer Center
- National Cancer Institute (P30 CA091842)
- National Institutes of Health (RO1AG013730, RO1NS065053, RO1NS087632)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- SARM1, Toll/interleukin-1 receptor domain, NADase activity, axonal degeneration, NAD+ depletion, ADP-ribose, axonal injury, traumatic axonal injury, axonopathy, therapeutic target
- MeSH terms
- Animals, Axons, Cells, Cultured, Cytoskeletal Proteins, Humans, NAD, NAD+ Nucleosidase, Nerve Degeneration, Mice, Knockout, Catalytic Domain, Armadillo Domain Proteins, Mice
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